Nonequivalence of classical MHC class I loci in ability to direct effective antiviral immunity

Kevin D. Pavelko, Yanice Mendez-Fernandez, Michael P. Bell, Michael J. Hansen, Aaron J. Johnson, Chella S. David, Moses Rodriguez, Larry R Pease

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Structural diversity in the peptide binding sites of the redundant classical MHC antigen presenting molecules is strongly selected in humans and mice. Although the encoded antigen presenting molecules overlap in antigen presenting function, differences in polymorphism at the MHC I A, B and C loci in humans and higher primates indicate these loci are not functionally equivalent. The structural basis of these differences is not known. We hypothesize that classical class I loci differ in their ability to direct effective immunity against intracellular pathogens. Using a picornavirus infection model and chimeric H-2 transgenes, we examined locus specific functional determinants distinguishing the ability of class I sister genes to direct effective anti viral immunity. Whereas, parental FVB and transgenic FVB mice expressing the H-2Kb gene are highly susceptible to persisting Theiler's virus infection within the CNS and subsequent demyelination, mice expressing the Db transgene clear the virus and are protected from demyelination. Remarkably, animals expressing a chimeric transgene, comprised primarily of Kb but encoding the peptide binding domain of Db, develop a robust anti viral CTL response yet fail to clear virus and develop significant demyelination. Differences in expression of the chimeric Kbα1α2Db gene (low) and Db (high) in the CNS of infected mice mirror expression levels of their endogenous H-2q counterparts in FVB mice. These findings demonstrate that locus specific elements other than those specifying peptide binding and T cell receptor interaction can determine ability to clear virus infection. This finding provides a basis for understanding locus-specific differences in MHC polymorphism, characterized best in human populations.

Original languageEnglish (US)
Article numbere1002541
JournalPLoS Pathogens
Volume8
Issue number2
DOIs
StatePublished - Feb 2012

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Antiviral Agents
Immunity
Demyelinating Diseases
Transgenes
Virus Diseases
Antigens
Picornaviridae Infections
Theilovirus
Viruses
MHC Class I Genes
Peptide T
T-Cell Antigen Receptor
Cell Communication
Primates
Transgenic Mice
Genes
Binding Sites
Peptides
Population

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Nonequivalence of classical MHC class I loci in ability to direct effective antiviral immunity. / Pavelko, Kevin D.; Mendez-Fernandez, Yanice; Bell, Michael P.; Hansen, Michael J.; Johnson, Aaron J.; David, Chella S.; Rodriguez, Moses; Pease, Larry R.

In: PLoS Pathogens, Vol. 8, No. 2, e1002541, 02.2012.

Research output: Contribution to journalArticle

Pavelko, Kevin D. ; Mendez-Fernandez, Yanice ; Bell, Michael P. ; Hansen, Michael J. ; Johnson, Aaron J. ; David, Chella S. ; Rodriguez, Moses ; Pease, Larry R. / Nonequivalence of classical MHC class I loci in ability to direct effective antiviral immunity. In: PLoS Pathogens. 2012 ; Vol. 8, No. 2.
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